Major depressive disorder (MOD) is a common and serious psychiatric illness. It is among the leading causes of disability and is the psychiatric disorder most frequently associated with suicide. Yet the treatment of MOD with antidepressant medication remains largely a trial-and-error process and little empirical evidence exists to guide treatment when suicide prevention is a priority. The purpose of this patient-oriented K-award is to develop and execute a program of research that will investigate clinical, neuropsychological and genetic predictors of response to different types of antidepressant medications in a high-risk sample of persons with MOD and a history of suicide attempt. Changes in clinical and neuropsychological components of depression and the diathesis for suicide will be compared during treatment with a serotonergic versus a non- serotonergic antidepressant. We will also determine whether functional polymorphisms in genes related to depression or the diathesis for suicide predict therapeutic effects of these antidepressants on mood or components of the diathesis for suicide. The principal investigator will carry out this program of research career development under the strong mentorship of Dr. J. John Mann (for training in the clinical neurobiology of depression and suicide). Active consultation and additional mentorship will come from Dr. A. John Rush (for training in antidepressant clinical trial design and execution), Dr. Bruce G. Pollock (for training in antidepressant pharmacogenetics), Dr. Joseph D. Terwilliger (for training in genetic epidemiology), Dr. John Keilp (for training in use of neuropsychological tests) and from Dr. Eva Petkova (for training in statistical analytic methods). This patient-oriented career development award will provide the principal investigator with the further experience and skills necessary to integrate clinical and scientific expertise in the field of depression and suicide clinical trials research. The long-term goal of this award is for the candidate to become an expert and independent clinical researcher on the treatment of depression with a special focus on suicide prevention.